Opioids are commonly prescribed because of their effective analgesic, or pain-relieving, properties. Medications that fall within this class, referred to as prescription narcotics, include morphine sulfate (e.g., Kadian®, Avinza™), codeine salts, oxycodone HCl (e.g., OxyContin™, Percodan™, Percocet™), and related drugs. For example, OxyContin™ tablets are presently commercially available in 10, 20, 40, 80, and 160 milligrams forms. Morphine, for example, is often used before and after surgical procedures to alleviate severe pain. Codeine, on the other hand, is often prescribed for mild pain. In addition to their pain-relieving properties, some of these drugs can be used to relieve coughs and diarrhea. Codeine and diphenoxylate (Lomotil™) are examples of such drugs. However, opioid drugs are at times associated with side effects including, e.g., stomach upset and other gastrointestinal effects. Further, because of the sometimes addictive properties of these drugs and the euphoria which can be associated with taking them, including through routes other than those prescribed, these opioid drugs are particular susceptible to abuse.
In order to reduce some of the gastrointestinal effects of these drugs, sustained release dosage forms have been described. For example, a sustained-release dosage form for morphine sulfate has been described [WO 2006/124898], in which a morphine sulfate core is coated with a matrix polymer insoluble at pH 1 to 7.5, an enteric polymer soluble at pH 6 to 7.5, and an acid soluble polymer which is soluble at pH 1 to 4, and having a ratio of acid soluble polymer to enteric polymer of 1.45:1 to 2.5:1 on a weight basis. Certain sustained release formulations are commercially available under the trademark Kadian® and are currently available in 20, 30, 50, 60 and 100 mg capsules.
Attempts to reduce abuse of opioid by pharmacological methods have been made. One such attempt involves including an “opioid antagonist” along with the opioid “agonist”. These antagonists cannot be easily extracted from the agonist and will cause an aversive effect in a physically dependent patient. However, these antagonists may have other side effects which may be disadvantageous.
One attempt to reduce opioid abuse and avoid the use of an agonist-antagonist combination has been described in US 2005/0163856A1, published Jul. 28, 2005. This patent application describes an oxycodone formulation designed to provide a pH independent release rate with a peak plasma level between 5-6 hours after administration. The formulation provides an oxycodone mixed with 40-65 wt % matrix forming polymer and 5 to 15 wt % of an ion exchange resin.
Ion exchange resins coated with a diffusion barrier coating have been described for the preparation of sustained release systems for preparing sustained release formulations. See, US-2006-0115529; WO 2006/101536; WO 2005/117843; US-2005-0265955 A1; WO 01/070194; U.S. Pat. Nos. 4,221,778, 4,996,047, and 4,861,598.
For example, U.S. Pat. No. 6,001,392 granted Dec. 14, 1999 describes certain acrylate based (e.g., EUDRAGIT polymer system) and ethyl cellulose (e.g., SURELEASE, AQUACOAT) polymers for coating a drug-ion exchange resin complex using either a solvent or aqueous based coating to achieve sustained release of the drug from the drug-ion exchange resin complex. There appears to be no meaningful data regarding the integrity of the coating film. Further, there is no data in the '392 patent of prolonged release of the drug from the coated drug-ion exchange resin complex beyond about 12 hours. There have been literature-reported drawbacks of using ethyl cellulose based aqueous dispersions as coatings for drug-ion exchange resin complexes.
Enteric coatings have been described as delayed release polymers for providing an initial delay in drug release. See, e.g., U.S. Pat. No. 6,756,057 for amoxicillin and U.S. Pat. No. 6,555,127 for methylphenidate. Enteric coatings are also used for protecting the body from drugs which cause gastric irritation (e.g., naproxen which is commercially available as enteric coated tablet and capsule formulations).
US-2006-0115529 and WO 2006/101536 describe the use of film coatings for a fast melt tablet containing ion exchange resin complex particles mixed with a dry binder and bulk diluent. One suitable coating described is the KOLLICOAT SR30D polymer system. Optional use of an enteric coat which is insoluble in acidic pH and soluble in basic pH is described.
US-2004-0126428 describes a product which is described as being abuse resistant. This product contains a core comprising a resonate of an opioid formed from the drug (e.g., morphine sulfate) and an ion exchange resin. A multi-component coating may also applied to the core, which contains (a) from 1 to 85% by weight of a matrix polymer which is insoluble at a pH of from 1 to 7.5 and contributes to the control of the rate of release of the active ingredient in the stomach and intestines; (b) from 1 to 30% of an enteric polymer which is substantially insoluble at a pH of from 1 to 4, sufficient to delay the release of the active ingredient in the stomach, but which is soluble at a pH of from 6 to 7.5 so as not to substantially delay release in the intestines; (c) from 1 to 60% of a compound soluble at a pH of from 1 to 4.
US 2003-0099711 A 1 describes using an ethyl cellulose polymer in an aqueous based coating system as a barrier coating. This publication further describes use of an optional enteric coating over the barrier coating to delay the drug release.
Opioid drug formulations which provide a desired sustained release profile without requiring an agonist-antagonist combination to reduce abuse are desirable from a commercial drug perspective.